Hypothesizing that a Pro-Dopaminergic Regulator (KB220z™ Liquid Variant) can Induce “Dopamine Homeostasis” and Provide Adjunctive Detoxification Benefits in Opiate/Opioid Dependence

In order to explore the initiation of detoxification of addictive patients to opiates/opioids (along with some other anti-withdrawal agents), we developed a protocol to be utilized in treatment centers particularly with heavily dependent opiate/opioid subjects. Out of 17 subjects, only three received Buprenorphine/Naloxone (Bup/nx) along with KB220Z. In this pilot, we first used a dose of KB220Z of 2 oz twice daily before meals along with clonidine and benzodiazepines and other anti-nausea and sleep aids including Gabapentin. The dose of KB220Z was maintained for 6 days in five individuals. In a second scenario, we utilized a higher dose of 4 oz every 6 hours, over a 6-day period. The higher dose was employed in another 12 patients. It is noteworthy that only 3 people have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The patients have been maintained without any additional Bup/nx for a minimum of 120 days and in one subject, 214 days. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates utilizing data from the Clinical opiate Withdrawal Scale (COWS) pre and post KB220Z. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates. While this does not constitute an acceptable controlled experiment, it does provide some preliminary evidence that agrees with an earlier study. Moreover, because of the utilization of standard detoxifying agents in this detoxification protocol, we cannot make any inference to KB220Z’s effects. However, out of 17 subjects, only three required Bup/nx suggesting an interesting finding. If further confirmed in larger studies, the utilization for opiate/opioid detoxification may provide a novel way to eliminate the need for addictive opioids during withdrawal and detoxification. This paradigm shift may translate to a reduction in utilizing powerful and addictive opioids like buprenorphine and methadone (especially in these patients at high genetic risk for addiction) as not only detoxifying agents, but also maintenance drugs. While extensive research is required, this pilot paves the way for future investigations that could assist in the reduction of addictive opiate/opioid use and mortalities amongst both the young and old in America.

In order to explore the initiation of detoxification of addictive patients to opiates/opioids (along with some other anti-withdrawal agents), we developed a protocol to be utilized in treatment centers particularly with heavily dependent opiate/opioid subjects. Out of 17 subjects, only three received Buprenorphine/Naloxone (Bup/nx) along with KB220Z. In this pilot, we first used a dose of KB220Z of 2 oz twice daily before meals along with clonidine and benzodiazepines and other anti-nausea and sleep aids including Gabapentin. The dose of KB220Z was maintained for 6 days in five individuals. In a second scenario, we utilized a higher dose of 4 oz every 6 hours, over a 6day period. The higher dose was employed in another 12 patients.
It is noteworthy that only 3 people have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The patients have been maintained without any additional Bup/nx for a minimum of 120 days and in one subject, 214 days. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates utilizing data from the Clinical opiate Withdrawal Scale (COWS) pre and post KB220Z. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates.

Introduction Opiate/Opioid epidemic
It is well-established that dopamine signaling is important in the reward pathway and that aberrations in the reward pathway are related to addiction and that by modulating dopaminergic signaling in the reward pathway, we could develop novel treatment modalities for addiction. We are hereby proposing that one way of potentially reducing the out-of control prescribing and subsequent illicit use of opiate/opioids in America is to consider the utilization of Pro-Dopamine Regulation with a nutraceutical complex called KB220Z.
While short-term use of Buprenorphine/Naloxone (Bup/nx) may have some benefit in the maintenance of opiate/opioid dependence, it is still a powerful addictive pharmaceutical that may reduce societal harm on one hand, but promotes addiction on the other hand. There has been a paucity of research related to opiate/opioid dependence withdrawal that evaluates non-addicting non-opiate safe detoxifying agents by promoting "dopamine homeostasis".
Medication-Assisted Treatment (MAT) is the use of FDA-approved medications, many of which are opioids, for the treatment of opiate/opioid addiction. Two major opioids used to treat opiate/opioid addiction are methadone and buprenorphine, in which the latter has been shown to be nearly 50 times more potent than morphine. Media reports and published drug/ addiction policy plans support a greater availability and use of Bup/nx combinations in addiction treatment [1]. Blum et al. have recently commented on raising the limits to 200 patients treated with Bup/nx combinations [2]. Most recently, beginning August 5, 2016, the ceiling will be lifted to 275.
These FDA-approved narcotics in opiate/opioid addiction treatment are definitively habit forming and consequently, addictive just like any other opiate or opioid. They are potentially equally dangerous and capable of the same abuse as any other prescription or illicit narcotic and there is the possibility of street diversion [3].
Previous work from our laboratory found that long-term Bup/nx use lead to blunted emotional responses in its users. Individuals reported less self-awareness of being happy, sad, and anxious. Over time, Bup/nxin effect caused a "zombie-like" effect on its users [4].
Moreover, Methadone was cited in nearly 13% of all the overdose deaths reported in the USA, up from about 4% five years earlier [5]. In 2012, Centers for Disease Control and Prevention (CDC) determined that Methadone was the culprit for one-third of U.S. prescription painkiller deaths. The CDC stated that while Methadone accounts for only 2% of painkiller prescriptions in the U.S., the drug accounts for more than 30% of prescription painkiller overdose deaths. Deaths from Methadone were found to be increasing as prescriptions for the drug rose [6]. The CDC also reported that in 2012, there were 41,502 deaths due to drug poisoning, or drug-overdose deaths, in the U.S.; 16,007 of these deaths involved opioids and 5,925 involved heroin [7].
Statistics provided by the CDC further indicate that 5,282 people died from an accidental overdose of methadone, while 5,925 died from heroin: a difference of 643 people within the same year. Despite empirical data that supports a pattern of increasing deaths attributed to Methadone, and also evidence that demonstrates slim difference between the number of Methadone versus heroin deaths (deaths that Methadone were said to prevent), the FDAapproved MAT narcotic is still widely prescribed, available, and deemed safe by the FDA and other advocates for treating opiate/opioid addicts with opiates/opioids. However, deaths attributed to Bup/nx are harder to track. According to a New York Times report in 2013, the CDC does not track buprenorphine deaths, neither do most emergency rooms, prisons, jails, drug courts, and the majority of medical examiners. A Times analysis of federal data showed that the drug was a "primary suspect" in 420 deaths reported to the FDA since its market availability in 2003. While this may not be medically relevant because of a news report, others have discussed this important issue [8].
To curtail psychoactive drug abuse and dependence, the FDA has approved a number of pharmaceutical agents that either reduce craving or suppress the pleasurable effect of drugs. While such agents have helped many patients, they have not prevented cravings and relapse completely. This fact is underlined by the recent findings that used data from the sophisticated Comprehensive Analysis of Reported Drugs (CARD ™ ). The study revealed a significant lack of "compliance" to various treatment medications and lack of "abstinence" from psychoactive drug use in both in-patient and outpatient treatment settings [9].
We agree that short-term use of MAT (possibly from detoxification to less than 12 months), especially Methadone or Bup/nx, may have important benefits regarding preventing unwanted opiate/opioid withdrawal. Moreover, these potent narcotics can induce patient stability ultimately leading to reinstatement of a patient into the workforce and become a socalled "productive member of society," and thereby, reducing societal harm. Understanding the neuropharmacology of MAT and dopaminergic mechanisms, in which blocking of dopamine induces "psychological extinction" (why use if the thrill is gone), is in our opinion, an inadequate and non-cost-effective way to combat America's second opiate/ opioid epidemic.

Outlining benefits of buprenorphine and naloxone combinations
Pharmacotherapy in conjunction with controlled withdrawal is currently the most reliable method of opioid detoxification. However, as translational medicine continues to advance and identify genomic markers for opioid sensitivity and dependence, the future holds potential for growth and change [10].
Bup/nx is an effective treatment therapy for opioid dependence and has similar efficacy to Methadone, although more data are needed. Less frequent dispensing of Bup/nx (e.g., thrice weekly) does not appear to compromise efficacy and can improve patient satisfaction. Bup/nx is more effective than clonidine as a medically supervised withdrawal therapy. Moreover, Bup/nx is a well-tolerated medically supervised withdrawal and maintenance treatment. Thus, sublingual Bup/nx is a valuable pharmacotherapy for the treatment of opioid dependence [11].
In another study, Ling et al. [12] compared the effects of a short or long taper schedule after buprenorphine stabilization on patient outcomes, which were measured by opioid-free urine tests at the end of each taper period. They observed that at the end of the taper, 44% of the 7day taper group (n = 255) provided opioid-free urine specimens, while 30% of the 28-day taper group (n = 261; P = 0.0007) provided opioid-free samples. In addition, there were no reported differences at the 1-month and 3-month follow-ups; the 7-day taper group resulted in 18% and 12% opioid-free specimens, and the 28-day taper group resulted in 18% and 13%, at the 1 month and 3 month follow-ups, respectively). Ultimately, the authors concluded that in individuals terminating buprenorphine pharmacotherapy for opioid dependence, there was no advantage in prolonging the duration of the taper.
While this study provides evidence for the clinical use of Bup/nx in the treatment of opioid withdrawal, as well as favoring short-term use, concerned scientists and clinicians must realize that we are, in essence, only substituting one narcotic for another powerful narcotic.
While Bup/nx is a standard in the treatment of opiate/opioid dependence, it is locking people into addiction. Understanding that Bup/nx induces severe withdrawal by itself, and possibly suicide ideation, we attempted to detoxify heavily addicted addicts without Bup/nx.

Characteristics and neuropharmacology of KB220 variants
With this introduction to the existing problem, we now carried out an experiment utilizing a well-researched amino-acid-enkephalinase inhibition therapy known [13] as Pro-Dopamine Regulator (PDR) for detoxification without the employment of buprenorphine alone or in combination with naloxone in 17 highly addicted opioid addicts. The rationale for the utilization of a KB220 nano-liquid variant is based on a plethora of literature as well as animal and human studies.
Specifically, the patented product is comprised of the following ingredients in validated, evidence-based intake levels: Thiamine, 15 mg (1033% of Daily Value); Vitamin B6, 10 mg (500%); Chromium polynicotinate (as Chrome Mate ® ), 200 mcg (166%); a fixed dose combination of amino acids and herbs called Synaptose ™ , which contains DL-Phenylalanine, L-Tyrosine, and Passion Flower Extract; a Metalloglycoside ™ Complex containing Arabinogalactans, N-Acetylglucosamine, Astragalus, Aloe Vera, Frankincense Resin, and White Pine Bark Extract; Rhodiola (as RhodiGen ™ ); L-Glutamine; 5-Hydroxytryptophan (5-HTP); Thiamine Hydrochloride; Pyroxidal-5-phosphate; and Pyridoxine HCl. The matching placebo powder is also manufactured by Cephram, Inc. (New Jersey). The resultant product utilized is an aqua, nano-liquid product developed in part by Aqua Power (Utah). The rational of the basic ingredients of KB220Z is provided in table 1. D 2 receptor activation, especially in the mesolimbic pathway, can be accomplished with "gentle" dopamine (DA) agonist therapy (PDR) involving receptor activation. One possibility is to utilize the nutraceutical complex, KB220Z (PDR), which in pre-clinical and clinical trials, has been shown to mirror the brain reward cascade to potentially induce "dopamine homeostasis." In an earlier unpublished, but submitted study, we observed the functional connectivity patterns between several brain structures and areas of the reward system under resting conditions in rats. Experiments were designed to test whether the observed resting state functional connectivity (rsFC) is influenced by administration of a putative dopaminergic agonist, KB220Z ™ [13].
To understand our rationale for evaluating KB220Z in the present study, we offer the following evidence for clinical benefit of neuromechanisms involved in producing dopamine homeostasis. KB220 variants (nutraceutical complex) have been extensively studied and tested [12]. As reported in detailed review articles [14,15], on both animals and humans to date, many references show that KB220 variants enhance brain enkephalin levels in rodents. Variants of KB220, also have the potential to reduce alcohol-seeking behavior in C57/BL mice and these variants can pharmacokinetically convert ethanol acceptance in preferring mice to non-preferring mice. In humans, KB220Z has demonstrated reduction of drug and alcohol withdrawal symptomatology (i.e., decreased need for benzodiazepines), fewer days with withdrawal tremors, evidence of a lower building up to drink (BUD) score, and elimination of severe depression on the Minnesota Multiphasic Personality Inventory (MMPI). In a double-blind placebo controlled study, patients in recovery treatment had reduced stress response (measured by the skin conductance level [SCL]), and significantly improved Physical Scores and behavioral, emotional, social and spiritual (BESS) scores. There was a six-fold decrease in American Medical Association (AMA) rates when comparing KB220 variants to placebo groups after detoxification. One-year relapse rates, for both cocaine and alcohol abusers, faired significantly better than known average relapse rates for these two psychoactive substances. Healthy volunteers demonstrated an enhanced focus ( Table 2).
There is also evidence of reduced craving for alcohol, heroin, cocaine, and nicotine. Also, reductions in inappropriate sexual behavior and reduced post-traumatic stress disorder (PTSD) symptoms, such as lucid nightmares, have been reported [16,17]. Quantitative electroencephalic (qEEG) studies in humans [18] have found that KB220Z modulates theta power in anterior cingulate cortex in abstinent psychostimulant abusers [19]. In abstinent heroin addicts, a single dose of KB220Z compared to placebo in a pilot study [20] resulted in activation of the Nucleus Accumbens (NAc) as well as activation and improvement of the prefrontal-cerebellar-occipital neural network. In addition, it was found that carriers with the DRD2 A1 allele showed a significant Pearson correlation in terms of enhanced compliance to KB220Z treatment relative to carriers of the normal compliment of DRD2 receptors in known obese patients [21]. This further suggests the importance of low dopamine function equating to better treatment outcome. These studies, including double-blinded control studies and others [22][23][24][25], have demonstrated positive effects on both craving attenuation and relapse prevention. Most recently, Steinberg et al. [26] showed increased activation of the anterior cingulate brain region using low-resolution brain electromagnetic tomography (LORETA) in attention-deficit/hyperactivity disorder (ADHD) patients.
In fact, it has been shown that DNA-directed compensatory overexpression of the DA D2 receptors (a form of gene therapy) results in a significant reduction in alcohol and cocaine craving behavior in drug-preferring rodents [27][28][29][30]. In addition, dopamine D 4 receptor knockout mice also predict future alcohol intake [31]. Moreover, in vitro bromocyrptine induced D 2 receptor proliferation in rats [32] causes a reduced D 2 receptor density in vivo chronically.
Achieving better treatment outcomes requires an understanding that the maintenance of steady "dopaminergic homeostasis" [33][34][35] is essential for achieving pleasurable experiences from ordinary daily activities and for relieving stress. Untreated impairments in the homeostatic balance of the DA signaling can facilitate aberrant substance-related disorders and process addictions [36] elucidated in former publications as Reward Deficiency Syndrome (RDS) [37,38]. The scientific research in this field is charged with the challenge of developing non-hazardous, non-addicting agents with dopaminergic upregulating agonistic properties.
As has been proposed previously, activation, rather than blocking, mesolimbic dopaminergic reward circuitry in the long-term treatment of RDS is the preferred modality even in treating hypersexuality [39,40]. Although, the acute treatment should consist of preferential blocking of postsynaptic NAc DA receptors (D 1 -D 5 ), the long-term mesolimbic activation of the dopaminergic system should involve the release and/or activation of DA at the NAc site. There must be focus on balancing the interaction of D 1 and D 2 receptor signaling.
This theory suggests that excessive craving behavior can be attributed to reduced number of DA D 2 receptors, an effect of carrying, for example, the DRD2 A1 allelic genotype; whereas a normal or sufficient density of D 2 receptors, including other normal genetic expressions such as Orexin and Pro-opiomelacortin (POMC), results in reduced craving and relapse and normal sleep patterns [41,42]. A goal, in terms of preventing substance abuse, could be to induce a proliferation of D 2 receptors in individuals who are genetically vulnerable. While in vivo experiments that use a typical D 2 receptor agonist induce down-regulation [43], in vitro experiments have shown that in spite of genetic antecedents, constant stimulation with a known D 2 agonist, bromocriptine, results in significant proliferation of D 2 receptors within the DA system, but chronic treatment of another D 2 receptor agonist, quinpirole, results in down-regulation, instead of up-regulation or balance proposed for KB220Z and that is a reason for failure in treatment [44].
Based on the current literature, new strategies are needed to treat RDS since the traditionally used therapeutic agents have had limited success in treatment of psychoactive substance abuse and relapse prevention and may require genetic testing leading to personalized medicine [45].

Rationale
As denoted above, we were compelled to design the current case series and we were optimistic because previous work in our laboratory suggested potential positive clinical outcomes. For example, in 1988, we found improvement in a double-blind evaluation of the nutritional supplement KB220 variant, in a 30-day inpatient alcohol and drug rehabilitation center [22]. The KB220 variant is uniquely designed to elevate levels of enkephalin (s), serotonin, and catecholamines, while balancing GABA, to offset functionally deficient neurotransmitters in alcoholics. Twenty-two patients were studied. The KB220 variant patients, as compared to the control group, (a) had a lower BUD score (1 vs. 2); (b) required no PRN benzodiazepines (0% vs. 94%); (c) ceased tremoring at 72 h, as compared to 96 h; and (d) had no severe depression on the MMPI, in contrast to 24% of the control group. These preliminary data suggest that KB220 variant is a valuable adjunct to therapy by aiding the patient's physical adjustment to a detoxified state, while facilitating a more positive response to behavioral therapy.
The second article that provided rationale for this experiment involved withdrawal from Bup/nx and maintenance with the putative dopamine agonist KB220 variant. Specifically, it was found that at 432 days post Bup/nx withdrawal, the patient was being maintained on KB220 and had been urine tested and was opioid free [1]. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait [1]. This preliminary case data suggest that the daily use of KB220 could provide a cost-effective alternative substitution adjunctive modality for Bup/nx. The authors encouraged double-blind randomized placebo-controlled studies to test the proposition that KB220 may act as a putative natural opioid substitution maintenance adjunct. More importantly, it is unknown if the KB220 variant could actually be used as a front-line detoxification agent.

Preliminary evidence of KB220Z liquid as an opiate/opioid detoxification agent
Certainly, there is a great need to find a way to detoxify patients addicted to opiates/opioids, without utilizing either methadone or any other opiate/opioid, including Bup/nx or buprenorphine alone. The main premise here is to detoxify these highly opiate/opioid addicted patients, who are possibly genetically prone to addictive behaviors, by providing endorphinergic-glutaminergic-dopaminergic balance [46] by employing KB220Z liquid variant.
In order to explore the possibility of initiation of detoxification of addictive patients to opiates/opioids (along with some other drugs), we developed a protocol to be utilized in treatment centers with heavily dependent opiate/opioid subjects. The experiment was approved by the PATH Foundation NY IRB committee, and consent forms were filled out by each patient enrolled in the study.
It is to be noted that a treatment center in Los Angeles, CA was selected for this pilot experiment. The center has detoxified many addicted patients and the staff utilizes a number of pharmaceuticals to assist in the detoxification process including: Buprenorphine alone, and in the combined form with naloxone in a 4:1 ratio; Escitalopram: Ondansetron, Gabapentin: Trazodone, Hydroxyzine: Duloxetine, Risperidone: Methocarbamol, Lamotrigine: Quetiapine, Lorazepam: Bupropion, Ketorolac: Clonidine. The doses of these drugs differed across the 17 patients. To determine if KB220z could replace Bup/nx in their regimen, the center carried out detoxification on a number of patients without the administration of Bup/nx by substituting KB220Z.
Out of 17 subjects, because of patient demand, only two received Bup/nx along with KB220Z. In this pilot, we first used a 2 oz dose of KB220Z twice daily before meals along with clonidine and benzodiazepines. The dose of KB220Z was maintained for 6 days in five individuals. In a second scenario, we utilized a higher dose of 4 oz every 6 hours over a 6day period. It was noted that the intensity of withdrawal symptoms as measured by the Clinical Opiate Withdrawal Scale COWS was reduced with the use of the higher dose. The higher dose was employed in additional12 patients.
It is noteworthy that only 3 subjects have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The subjects have been maintained without any additional Bup/nx for a minimum of 120 days. However, one patient, a 21-year-old female addicted to methadone and amphetamines, has now been maintained on just KB220Z for about 7 months (Table 3). After 120-day period, the other subjects were no longer followed up, so we are unable to determine how long they have remained on KB220Z. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates.
The following demographics are provided for the initial five patients taking the lower 2 oz dose of KB220Z twice daily, and then maintained on ½ oz of KB220Z twice daily for at least 120 days. The importance here is that during the detoxification period of 6 days, none of these patients required Bup/nx. The center reported that the withdrawal symptomatology was not intense for any of these five patients (Table 3). Unfortunately, these patients have not been followed for the past 120 days, except for the patient cited above. The intensity of withdrawal was assessed by the attending staff and self-reported as well. In a follow-up study we will be able to quantitative the severity of withdrawal symptoms on a larger cohort compared to patients undergoing opiate/opioid withdrawal without KB220Z variant. Until this additional required study is performed we must cautiously interpret this pilot experiment.
As we mentioned the dose for anti-withdrawal pharmaceuticals varied with each patient and to address this issue the following dosage is provided for the five initial participants. Similar dosage was obtained for the additional 12 participants: Demographics on the additional 12 patients are available from the treatment center and could be retrieved on request by contacting the corresponding author of this article.

Limits
While this does not constitute an acceptable controlled experiment, it does provide some preliminary evidence that agrees with our earlier case study as previously discussed above, whereby utilizing KB220Z in the nano pill form in a female patient who was maintained opiate/opioid free as measured by a drug-urine screen for at least 432 days [1]. In this earlier study, we could not provide the patient with KB220Z because unlike the liquid form, the patient could not tolerate the pill during intensive withdrawal.
While these results are somewhat encouraging, they do not provide adequate information concerning the real benefit of KB220Z in its liquid form, other than it was safe and easy to take during drug withdrawal when compared to previous tablet forms. Moreover, because of the utilization of a number of standard detoxifying agents utilized in this detoxification protocol, we cannot make any inference to KB220Z's effects. However, out of 17 patients, only two required Bup/nx suggesting an interesting finding, whereby if further confirmed in larger studies may provide a novel way to eliminate the need for addictive opioids during withdrawal and detoxification followed by maintenance with KB220Z. This must be considered as a pilot and we caution against any interpretation of these preliminary results.

Discussion
This is the first case report concerning liquid KB220Z and detoxification of known opiate/ opioid dependent individuals. In the current study, we decided to evaluate the effect of KB220Z in a nano-liquid with regard to opioid withdrawal symptomatology in 17 patients with a primary diagnosis of drug addiction to opioids or amphetamines/methamphetamine or a combination thereof. The intent of this pilot study was an attempt to withdraw these patients without the use of buprenorphine alone or in combination of naloxone (Bup/nx).
We are cognizant of the important utility of Bup/nx in the short-term treatment of opiate/ opioid addiction. It is well known that Bup/nx is a partial μ-opioid agonist combined with the opioid antagonist naloxone in a 4:1 ratio. According to some [47], this combination is safe and beneficial to treat illicit and prescription-opioid dependence. Bup/nx has a lower abuse potential, carries less stigma, and allows for more flexibility than methadone. Bup/nx is indicated for in-patient, ambulatory medically assisted withdrawal (acute detoxification), and long-term substitution treatment (maintenance) of patients who have a mild-to-moderate physical dependence. A stepwise long-term substitution treatment with regular monitoring and follow-up assessment is usually preferred, as it has better outcomes in reducing illicit opioid use, minimizing concomitant risks such as human immunodeficiency virus and hepatitis C transmission, retaining patients in treatment, and improving global functioning. While this seems like a very plausible treatment option approved by the FDA, it is rift with long-term problems as outlined by a number of reports [1,3,15,[48][49][50][51].
Medically supervised opioid withdrawal is a complex and constantly evolving exercise in multimodal therapy that draws from the expertise of a variety of clinical specialties. In a number of studies to date, it has been reported that acute substitution and weaning off of opioids has been performed utilizing opioid agonists, partial agonists (e.g., buprenorphine), mixed agonist/antagonists (e.g., Bup/nx), and α2 adrenergic agonists with some success.
While thousands of patients are being treated with these 'classic' opioid-withdrawal techniques, traditional treatment approaches are being challenged by the emergence of innovative techniques based on an understanding of the neurochemistry of addiction [49,50,52]. Most importantly, Blum's earlier experiment showing a significant reduction of alcohol withdrawal in a residential United Sates recovery and treatment center has been further validated in this pilot study [22].

Conclusion
In this pilot observational study, it is noteworthy that only 3 people have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The patients have been maintained without any additional Bup/nx for a minimum of 120 days and in one subject, 214 days. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates utilizing data from the Clinical opiate Withdrawal Scale (COWS) pre and post KB220Z.
In summary, it is our hypothesis that future steps to overcome the current opiate/opioid epidemic in the United States claiming at least 127 people dying every day from narcotic overdoses must consider newer and better ways to not only detoxify individuals from prescription opioids like methadone and buprenorphine, but induce "dopamine homeostasis" as a maintenance goal free of any opiates/opioids. This is easily said, but may be difficult in practice. In this regard, we encourage additional research in this most perplexing area. Table 1 List of KB220Z Ingredients with targets and mechanism of action. Cognitive processing speeds in normal young adult volunteers were measured before and after 28-30 days of supplementation with a combination of amino acids (NAAT), vitamins, and minerals. Cognitive processing speeds were enhanced by a statistically significant amplitude of the P300 component of the Event Related Potentials (ERPs). Focus improved.
Blum K, et al. [61] Of 247 outpatients in a very-low-calorie fasting program, 130 who were having difficulty attaining their desired weight or maintaining their desired weight, constituted the experimental group who took PhenCal ™ and of the rest, 117 took vitamins and 117 were the control group. The PhenCal ™ group compared to the control lost twice as much weight, regained 14.7% of the weight, while the control group regained 41.7%, decrease in food cravings for females 70% and males 63%, and decreased in binge eating for females 66% and males 41%.

2001
Ross J, et al. [62] Preliminary evaluation of six randomly selected former eating disorder female clients (three were also chemically dependent), contacted at 9 months, and 3 years of treatment with amino-acid precursor and enkephalinase inhibition therapy. All 6 reported initial benefit, one relapsed at 6 months, the other 5 all sustained, and in some cases exceeded expectations. 98% of 100 patients similarly treated and evaluated reported significant improvement in both mood and reduced substance craving.

2004
Chen TJ, et al. [63] A combination of Trexan (a narcotic antagonist) and amino-acids was use to detoxify either methadone or heroin addicts. Results were dramatic in terms of significantly enhancing compliance to continue taking Trexan. Trexan alone for rapid detoxification, the average number of days of compliance calculated on 1000 patients is 37 days. 12 subjects tested, receiving both the Trexan and amino-acid therapy, taking the combination for an average of 262 days. Suggests coupling amino-acid therapy and enkephalinase inhibition, while blocking the delta-receptors with a pure narcotic antagonist as a novel method to induce rapid detox in chronic methadone patients and prevent relapse, and testing this hypothesis with the sublingual combination of the partial opiate mu receptor agonist buprenorphine.

2006
Blum K, et al. [64] Consumption of large quantities of alcohol or carbohydrates (carbohydrate bingeing) stimulates production and usage of dopamine within the brain. Obesity is due to the need to make up for inadequate dopaminergic activity Lucid dreams may be associated with psychiatric conditions, including Post-Traumatic Stress Disorder (PTSD) and Reward Deficiency Syndrome-associated diagnoses. We present two cases of dramatic alleviation of terrifying lucid dreams in patients with PTSD. The medication visit notes reveal changes in the frequency, intensity, and nature of these dreams after the complex putative dopamine agonist KB220Z was added to the first patient's regimen. The second PTSD patient, who had suffered from lucid nightmares, was administered KB220Z to attenuate methadone withdrawal symptoms and incidentally reported dreams full of happiness and laughter.
McLaughlin T, et al. [17] Lucid dreams could be unpleasant or terrifying, at least in the context of patients who also exhibit characteristics of Reward Deficiency Syndrome (RDS) and Post-Traumatic Stress Disorder (PTSD). We present eight clinical cases, with known substance abuse, childhood abuse, and diagnosed PTSD/RDS. The administration of a putative dopamine agonist, KB200Z ™ , was associated with the elimination of unpleasant and/or terrifying, lucid dreams in 87.5% of the cases presented, whereas one very heavy cocaine abuser showed a minimal response. These results required the continuous use of this nutraceutical. If these results, in a small number of patients are indeed confirmed, we may have found a frontline solution to a very perplexing and complicated symptom known as lucid dreams.
Blum K, et al. [20] Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D 2 /D 3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow et al. KB220Z induced an increase in BOLD activation in caudate-accumbensdopaminergic pathways compared to placebo following 1-hour acute administration in abstinent heroin addicts. Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. Results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction.

2016
McLaughlin T, et al. [75] The four patients initially reported a gradual but, then, complete amelioration of their long-term, terrifying, lucid dreams, while taking KB220Z. The persistent amelioration of these dreams continued for up to 12 months, after KB220Z. These particular cases raise the scientific possibility that KB200Z increases both dopamine stability as well as functional connectivity between networks of brain reward circuitry in both rodents and humans. In order to attempt to understand the possibility of neuroplasticity, we evaluated the effect of KB220Z in non-opioidaddicted rats utilizing functional Magnetic Resonance Imaging methodology. While we cannot make a definitive claim because rat brain functional connectivity may not be exactly the same as humans, it does provide some interesting clues. We did find following seeding of the dorsal hippocampus, enhanced connectivity volume across several Regions of Interest (ROI), with the exception of the pre-frontal cortex. Interestingly, the latter region is only infrequently activated in lucid human dreaming, when the dreamer reports that he/she had the thought that they were dreaming during the lucid dream.
Harriet Beitscher-Campbell, et al. [76] While there are still a number of scientists that would argue the commonality between these two seemingly diverse substances, the field is rift with many neuroscience imaging studies that show a neurochemical commonality as well as other genetic studies showing a hypodopaminergic trait. While we did not provide evidence showing any potential difference among those with anorexia nervosa, binge eating disorder, bulimia nervosa, sub-threshold bingeing, we are reporting at a minimum co-morbidity with eating disorders and SUD.
Here we show fifty case reports derived from two independent treatment centers in Florida, that suggest the commonality between food and drug addiction.